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New Human On Chip Technology Permits Unparalleled Insight into the Dynamics of Cellular Function

04-04-2016

Hebrew University’s liver-on-chip platform is uniquely able to monitor metabolic changes indicating mitochondrial damage occurring at drug concentrations previously regarded as safe

Mitochondrial dysfunction plays a critical role in the development of chemical and pharmaceutical toxicity. However, current methods to evaluate mitochondrial activity still rely on traditional tests called end-point assays, which provide limited prognostic information.

Microfluidic organ-on-a-chip technology, which uses microchip-manufacturing methods to arrange living cell cultures to simulate the physiology of tissues and organs, is poised to replace drug toxicity testing in animals, but thus far has demonstrated few advantages over traditional methods and animal experiments.

Now, researchers from The Hebrew University of Jerusalem describe a new generation of Liver on Chip devices, in which the researchers add glucose and lactate micro-sensors, allowing them to measure minuscule changes in central carbon metabolism in real time (seconds to minutes). 

The robust microfluidic platform is composed of sub-millimeter human tissues, which the authors characterize as “bionic” as they contain optoelectronic sensors for oxygen and are maintained under conditions simulating the human physiological environment. The platform includes a computer-controlled switchboard and permits the automated measurement of glucose and lactate using clinical-grade micro-sensors. The sensor-integrated platform permits real-time tracking of the dynamics of metabolic adaptation to any type of mitochondrial damage for over a month in culture.

The study, entitled “Real-time Monitoring of Metabolic Function in Liver-on-Chip Microdevices Tracks the Dynamics of Mitochondrial Dysfunction,” appears in the Proceedings of the National Academy of Sciences

“Central carbon, or glucose and amino acid, metabolism is by far the most important source of energy and materials for our cells. It is the backbone of cellular function,” said the study’s lead author Prof. Yaakov Nahmias, Director of the Alexander Grass Center for Bioengineering at the Hebrew University of Jerusalem. Otto Warburg recognized the importance of changes in central carbon metabolism to cancer development back in 1924, and more recent studies tied alterations in this pathway to the emergence of stem cells. “This metabolic pathway is very sensitive, and any toxic damage will either directly or ultimately lead to changes in glucose metabolism,” said Nahmias.

This approach already enabled Nahmias and his team to identify a new mode of acetaminophen (Tylenol®) toxicity back in June, suggesting the drug could directly block respiration in the kidneys and skin.

In the current research, the team used an array of micro-sensors to measure small changes in metabolic fluxes. In other words, the sensor-integrated “bionic” micro-livers actively told researchers how they change their metabolic pathways (what they “eat,” “digest” and “spew out”) when exposed to new drugs. 

This allows researchers to identify new causes for idiosyncratic toxicity, one of the biggest problems in drug discovery and the main cause for post-market drug withdrawal. 

Idiosyncratic toxicity occurs without obvious reason to about 1:100,000 in the population, forcing new warning labels or complete withdraw of the drug (costing billions). 

The researchers tested the new technology on troglitazone (Rezulin®), an anti-diabetic and anti-inflammatory drug which was removed from the US market in 2000 due to severe drug-induced liver injury, costing Pfizer Inc. over $750 million in lawsuits. 

The results showed that even at low troglitazone concentrations previously regarded as safe, in which traditional tests don’t reveal any damage to the cells, the new liver-on-chip technology was able to detect mitochondrial stress that forces the liver to increase its reliance on glucose metabolism. 

By revealing the dynamics of cellular adaptation to mitochondrial damage, this novel organ-on-chip technology permits detection of chemical toxicity before any effects on cell or tissue viability can be observed.

Prof. Nahmias said: “The ability to measure metabolic fluxes using small numbers of cells under physiological conditions can redefine the study of neurodegenerative disease, stem cells and cancer, in addition to drug discovery. In contrast to other instruments, such as the SeaHorse Flux Analyzer, our sensors do not require calibration and our cells do not undergo hypoxia or become exposed to decaying chemical signals due to non-specific absorption. Our microfluidic system could be of significant interest to biological and clinical laboratories, whose work can range from the study of mitochondria and oxidative stress in neurological disorders (Alzheimer’s, Parkinson’s), to metabolic disease (diabetes, obesity), stem cell biology (pluripotency), virology and cancer.”

Dr. Daniel Duche, former head of the Early Safety Laboratory, unit of the Predictive Models and Methods Development Department of L’Oréal Research & Innovation, said: “The work performed by Y. Nahmias’s team demonstrates that it becomes possible to monitor dynamically in real time metabolic functions of cells exposed to different drug concentrations over a long period using organ-on-chip microdevices. That helps to define Adverse Outcome Pathways and brings a real breakthrough in the in vitro alternative methods to animal experimentation for evaluating toxicity of chemicals.”

 

Latin American Academic Leaders Visit Israel, Sign Cooperation Agreements with Hebrew University

Some twenty rectors from leading Latin American universities visited Israel this week and signed agreements with the Hebrew University of Jerusalem, in a first-of-its-kind conference signalling growing academic cooperation

15-12-2016

Higher BMI in Adolescence May Affect Cognitive Function in Midlife

Study of Israeli adolescents also looks at impact of socioeconomic position on subsequent cognitive impairment

08-12-2016

A New Passion Fruit Variety Keeps the Brain Young

Hebrew University Researchers Develop a New Strain of Passion Fruit that significantly protects brain cells and its function from aging-related damage

08-12-2016

Best History Book France 2016

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Hebrew University Congratulates Researchers On Receiving 2016 EMET Prize

Hebrew University Researchers Bring Home 3 of the 8 EMET Prizes Awarded for 2016

04-12-2016

The Bert and Ernie Principle of Sharing:

When and Why Do Children Give Others the Bigger Piece of the Pie?

29-11-2016

Researchers uncover a survival mechanism in cancer cells

Scientists from the Crick Institute, London and the Hebrew University, Jerusalem, discover a protein that plays a key role in turning cancer tumour cells into cancer stem cells that are able to renew outbreaks of the disease

22-11-2016

Hebrew University Students Ranked the 67th Most Employable Worldwide

An analysis of graduates employability published by Times Higher Education (THE) has ranked graduates of the Hebrew University of Jerusalem as the 67th most employable in the world.

20-11-2016

Canada's Governor General Visits Hebrew University's Faculty of Medicine

Governor General discusses collaborative medical research partnerships between Canada and Israel at IMRIC, the Institute for Medical Research Israel-Canada

03-11-2016

Italian President Sergio Mattarella Visits the Hebrew University of Jerusalem

On the first day of his state visit to Israel, the President of the Italian Republic, Sergio Mattarella, gave a keynote address to an overflow audience, at the Truman Institute on the university's Mount Scopus campus.

30-10-2016

The Hebrew University European Brain Forum 'Brain & Pain'

Sunday 20th November: 10:30 - 17:00 Paris

27-10-2016

Strategic Partnership between the Hebrew University and the University of Vienna

Four joint seminars took place, where scientists from the Hebrew University and the University of Vienna met to exchange ideas and to prepare proposals for third party funding

27-10-2016

Limmud Conference 2016

Deborah Steinmetz, Director, Steven Spielberg Jewish Film Archive

18-10-2016

Scientists Find New Metabolic Pathways to Resist Viruses

International partnership unravels the mechanism by which Hepatitis C Virus (HCV) reprograms human metabolism, and identifies new pathways of anti-viral resistance

10-10-2016

Groundbreaking Immune Approach Targets Humans Instead of Bacteria

Scientists show for the first time how bacterial superantigen toxins work, and how short peptides can block them and save lives

06-10-2016

Asian Religious Leaders Discuss Peace, Environment With Israeli Counterparts at Hebrew University

A delegation of Asian religious leaders visited the Hebrew University of Jerusalem

13-09-2016

Hebrew University Launches Israel’s First Academic Degree Programme in Viticulture and Enology

Innovative boutique programme for professional training in the growth, production and analysis of wine, as well as wineries management

17-08-2016

New Chair of the Young Professionals Group

Succeeding Jacqueline Caspi as Chair of the BFHU Young Professional Committee is Benjamin Stowe

16-08-2016

Rare Frescoes from Roman Period Discovered in Hebrew University Excavations at Zippori in Galilee

New finds contribute significantly to research of Roman art in Israel: Provide first evidence of figurative images in wall paintings at the site, and precede earliest mosaics discovered at the site by a hundred years

10-08-2016

Historic Find at Tel-Hazor: A Statue of an Egyptian Official

In a historic find, a large fragment of an Egyptian statue measuring 45 X 40 centimetres, made of lime-stone, was discovered In the course of the current season of excavations at Tel-Hazor, north of the Sea of Galilee in Israel

25-07-2016

IMRIC Scientist Awarded for Work in Stem Cells & Regenerative Medicine

Dr. Yosef Buganim is a young researcher at the Institute for Medical Research Israel-Canada (IMRIC), part of the Hebrew University's Faculty of Medicine

18-07-2016

Single Dose of Novel Peptide Protects Cognitive Function after Mild Traumatic Brain Injury

New molecules, developed by Hebrew University of Jerusalem scientists, reduce inflammation, cell death and cognitive impairments following traumatic brain injury in mice

11-07-2016

Hebrew University #1 in Middle East, #26 Worldwide, Says Saudi-based Centre

The Centre for World University Rankings (CWUR), based in Saudi Arabia, has ranked the Hebrew University of Jerusalem at #26 among the 25,000+ degree-granting institutions in the world.

11-07-2016

European Neuroscience Outreach Award

Goes to Hebrew University's ELSC Brain Sciences Centre

07-07-2016

Dame Helen Mirren Meets Arab and Jewish Students at Hebrew University

Dame Helen Mirren, one of the world's best-known and most respected actresses, met with Arab and Jewish theatre students at The Billy Crystal Program for Peace Through the Performing Arts

26-06-2016

Hebrew University Ranked #17 in Asia, First in Israel, in 2016

Times Higher Education Asia University Rankings Editor of Times Higher Education Rankings: "It has never been as clear to me that the balance of power is shifting from the West to the East."

20-06-2016

Prof. Rina Talgam Awarded the Polonsky Prize

Historical survey of excavated mosaic art of pagans, Jews, Samaritans, Christians and Muslims earns Hebrew University professor the first prize in this year's Polonsky Awards

08-06-2016

A New Immunotherapy against Cancer Earns a Hebrew University Researcher the Kaye Innovation Award

Pinchas Tsukerman developed a novel immunotherapy method in which monoclonal antibodies neutralize the tumor's ability to suppress the immune system

07-06-2016

Israeli President Reuven Rivlin at Hebrew University Convocation:

'Striving to expand the government is correct and justified.' President Rivlin, a Hebrew University alumnus, praises academia's role as unifier of Israeli society

29-05-2016

Young Professional Group hosted a dinner in the House of Lords

The British Friends of The Hebrew University Young Professional Group has held its first dinner. The dinner was hosted by Lord Pannick QC in the Peers' Dining Room, House of Lords

26-05-2016

President Rivlin, a Hebrew University alumnus, to deliver keynote address

Israeli President Reuven Rivlin, American Jewish Philanthropist Mortimer B. Zuckerman, and i24 founder Patrick Drahi To Be Honored at Hebrew University Convocation

22-05-2016

University of Toronto and the Hebrew University of Jerusalem Deepen Ties

The University of Toronto and The Hebrew University of Jerusalem are pleased to deepen their partnership in the fields of social work and bio-innovation

19-05-2016

Prime Minister of Singapore Begins Official Visit to Israel at the Hebrew University of Jerusalem

Hebrew University signs agreements with leading academic institutions from the Republic of Singapore, and confers honorary doctorate upon Prime Minister Lee Hsien Loong

18-04-2016

New Human On Chip Technology Permits Unparalleled Insight into the Dynamics of Cellular Function

Hebrew University's liver-on-chip platform is uniquely able to monitor metabolic changes indicating mitochondrial damage occurring at drug concentrations previously regarded as safe

04-04-2016

Yissum Showcases Hebrew University’s Breakthroughs in Advanced Materials and Nanotechnology

Yaacov Michlin, CEO, Yissum: During 2015, Yissum founded a record number of eight companies based on inventions of researchers from the Hebrew University Centre for Nanoscience and Nanotechnology

31-03-2016

President Pavlopoulos of Greece Awarded Hebrew University Honorary Doctorate

His Excellency the President of the Hellenic Republic, Mr. Prokopios Pavlopoulos, was awarded an honorary doctorate by the Hebrew University of Jerusalem.

30-03-2016

Yissum takes part in project to Operate a Tech Incubator under Israel's National Incubator Programme

Jerusalem Venture Partners (JVP) LED Group joins forces with Motorola Solutions (NYSE: MSI), Reliance Industries (NSE: Reliance) and Yissum, the Research Development Company of the Hebrew University of Jerusalem

22-03-2016

Scientists Generate a New Type of Human Stem Cell That Has Half a Genome

The haploid stem cells may yield new genetic screening tools and therapies

16-03-2016

New method detects multiple diseases via DNA released from dying cells into blood

New blood test uses methylation patterns of circulating DNA from dying cells to detect diabetes, multiple sclerosis, pancreatic cancer, pancreatitis and brain damage, opening up vast possibilities for diagnostic medicine.

14-03-2016

Yissum

The Technology Transfer Company of the Hebrew University, comes to London

10-03-2016

The Hebrew University of Jerusalem to Name School of Education in Honour of Former Head Seymour Fox

Dedication Ceremony and Memorial Lecture on March 14 on Mount Scopus

10-03-2016

New Device Shortens Chest-Tube Insertion From Minutes To Seconds

Hebrew University students develop life-saving device following a wave of stabbing attacks that leaves some civilians with collapsed lungs

09-03-2016

Cellular Aging Process Unexpectedly Enhances Insulin Secretion

Researchers find that a cell aging program causes human and mouse pancreatic beta cells to work harder and secrete more insulin

07-03-2016

Scientists "break the ice" on organ banking

Hebrew University researchers develop a solution for long-term preservation of cells and organs for transplant, as part of a global alliance to bank organs

02-03-2016

Nanotechnology delivery system offers new approach to skin disease therapies

Hebrew University formula that activates the body's natural defense against free radicals could control a variety of skin pathologies and disorders

29-02-2016

Optical Guide Aims To Keep Orthopaedic Procedures Right On Target

New fibre optic guide-wire will enable surgeons to perform highly accurate hip fracture and spinal fusion surgery with minimal side effects

23-02-2016

Rare Einstein Documents Related To Historic Gravity Announcement Displayed at Hebrew University

Scientists At NSF Press Conference in D.C. Confirm Einstein's Century-Old Prediction

11-02-2016

The 2016 Institute for Law and Policy at The Hebrew University Faculty of Law

Three-Week Summer Program for International Students and Attorneys Opens June 27, 2016

08-02-2016

Hebrew University Linguist Prof. Edit Doron to be Awarded Israel Prize

Israeli Minister of Education Naftali Bennett has announced that Prof. Edit Doron will be awarded the Israel Prize for her work in the study of Linguistics.

03-02-2016

Hebrew University Researchers Led Israel With 14 ERC Grants from EU in 2015

Over 23,000,000 Euros to Promote Groundbreaking Research in Medicine, Mathematics & Sciences, and the Humanities

07-01-2016

The British Friends turn 90 years old!

Supporting the Hebrew University since 1926

05-01-2016
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